Abstract
Topoisomerase I (Top1) resolves torsional stress that accumulates during transcription, replication and chromatin remodeling by introducing a transient single-strand break in DNA. The cleavage activity of Top1 has opposing roles, either promoting or destabilizing genome integrity depending on the context. Resolution of transcription-associated negative supercoils, for example, prevents pairing of the nascent RNA with the DNA template (R-loops) as well as DNA secondary structure formation. Reduced Top1 levels thus enhance CAG repeat contraction, somatic hypermutation, and class switch recombination. Actively transcribed ribosomal DNA is also destabilized in the absence of Top1, reflecting the importance of Top1 in ensuring efficient transcription. In terms of promoting genome instability, an aborted Top1 catalytic cycle stimulates deletions at short tandem repeats and the enzyme’s transesterification activity supports illegitimate recombination. Finally, Top1 incision at ribonucleotides embedded in DNA generates deletions in tandem repeats, and induces gross chromosomal rearrangements and mitotic recombination.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413. https://doi.org/10.1146/annurev.biochem.70.1.369
Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3(6):430–440. https://doi.org/10.1038/nrm831
Pommier Y, Sun Y, Huang SN et al (2016) Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat Rev Mol Cell Biol 17(11):703–721. https://doi.org/10.1038/nrm.2016.111
Liu LF, Wang JC (1987) Supercoiling of the DNA template during transcription. Proc Natl Acad Sci U S A 84(20):7024–7027
Wu HY, Shyy SH, Wang JC et al (1988) Transcription generates positively and negatively supercoiled domains in the template. Cell 53(3):433–440
Tanizawa A, Kohn KW, Pommier Y (1993) Induction of cleavage in topoisomerase I c-DNA by topoisomerase I enzymes from calf thymus and wheat germ in the presence and absence of camptothecin. Nucleic Acids Res 21(22):5157–5166
Been MD, Burgess RR, Champoux JJ (1984) Nucleotide sequence preference at rat liver and wheat germ type 1 DNA topoisomerase breakage sites in duplex SV40 DNA. Nucleic Acids Res 12(7):3097–3114
Shuman S, Prescott J (1990) Specific DNA cleavage and binding by vaccinia virus DNA topoisomerase I. J Biol Chem 265(29):17826–17836
Pourquier P, Ueng LM, Kohlhagen G et al (1997) Effects of uracil incorporation, DNA mismatches, and abasic sites on cleavage and religation activities of mammalian topoisomerase I. J Biol Chem 272(12):7792–7796
Pommier Y, Barcelo JM, Rao VA et al (2006) Repair of topoisomerase I-mediated DNA damage. Prog Nucleic Acid Res Mol Biol 81:179–229. https://doi.org/10.1016/S0079-6603(06)81005-6
Schultz MC, Brill SJ, Ju Q et al (1992) Topoisomerases and yeast rRNA transcription: negative supercoiling stimulates initiation and topoisomerase activity is required for elongation. Genes Dev 6(7):1332–1341
Fernandez X, Diaz-Ingelmo O, Martinez-Garcia B et al (2014) Chromatin regulates DNA torsional energy via topoisomerase II-mediated relaxation of positive supercoils. EMBO J 33(13):1492–1501. 10.15252/embj.201488091
Salceda J, Fernandez X, Roca J (2006) Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA. EMBO J 25(11):2575–2583. https://doi.org/10.1038/sj.emboj.7601142
French SL, Sikes ML, Hontz RD et al (2011) Distinguishing the roles of topoisomerases I and II in relief of transcription-induced torsional stress in yeast rRNA genes. Mol Cell Biol 31(3):482–494. https://doi.org/10.1128/mcb.00589-10
Staker BL, Hjerrild K, Feese MD et al (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A 99(24):15387–15392. https://doi.org/10.1073/pnas.242259599
Tomicic MT, Kaina B (2013) Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta 1835(1):11–27. https://doi.org/10.1016/j.bbcan.2012.09.002
Colley WC, van der Merwe M, Vance JR et al (2004) Substitution of conserved residues within the active site alters the cleavage religation equilibrium of DNA topoisomerase I. J Biol Chem 279(52):54069–54078. https://doi.org/10.1074/jbc.M409764200
Andersen SL, Sloan RS, Petes TD et al (2015) Genome-destabilizing effects associated with Top1 loss or accumulation of Top1 cleavage complexes in yeast. PLoS Genet 11(4):e1005098. https://doi.org/10.1371/journal.pgen.1005098
Sloan RS (2016) Topoisomerase 1 (Top1)-associated genome instability in yeast: effects of persistent cleavage complexes or increased Top1 levels. Dissertation, Duke University
Husain I, Mohler JL, Seigler HF et al (1994) Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res 54(2):539–546
Pfister TD, Reinhold WC, Agama K et al (2009) Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity. Mol Cancer Ther 8(7):1878–1884. https://doi.org/10.1158/1535-7163.mct-09-0016
Shamanna RA, Lu H, Croteau DL et al (2016) Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. Oncotarget 7(12):13269–13284. 10.18632/oncotarget.7906
Koster DA, Palle K, Bot ES et al (2007) Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448(7150):213–217. https://doi.org/10.1038/nature05938
Ray Chaudhuri A, Hashimoto Y, Herrador R et al (2012) Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol 19(4):417–423. https://doi.org/10.1038/nsmb.2258
Yang SW, Burgin AB Jr, Huizenga BN et al (1996) A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci U S A 93(21):11534–11539
Debethune L, Kohlhagen G, Grandas A et al (2002) Processing of nucleopeptides mimicking the topoisomerase I-DNA covalent complex by tyrosyl-DNA phosphodiesterase. Nucleic Acids Res 30(5):1198–1204
Stingele J, Schwarz MS, Bloemeke N et al (2014) A DNA-dependent protease involved in DNA-protein crosslink repair. Cell 158(2):327–338. https://doi.org/10.1016/j.cell.2014.04.053
Balakirev MY, Mullally JE, Favier A et al (2015) Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates. elife 4. https://doi.org/10.7554/eLife.06763
Vance JR, Wilson TE (2001) Uncoupling of 3′-phosphatase and 5′-kinase functions in budding yeast. Characterization of Saccharomyces cerevisiae DNA 3′-phosphatase (TPP1). J Biol Chem 276(18):15073–15081. https://doi.org/10.1074/jbc.M011075200
Vance JR, Wilson TE (2001) Repair of DNA strand breaks by the overlapping functions of lesion-specific and non-lesion-specific DNA 3′ phosphatases. Mol Cell Biol 21(21):7191–7198. https://doi.org/10.1128/mcb.21.21.7191-7198.2001
Weinfeld M, Mani RS, Abdou I et al (2011) Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair. Trends Biochem Sci 36(5):262–271. https://doi.org/10.1016/j.tibs.2011.01.006
Xu Y, Her C (2015) Inhibition of topoisomerase (DNA) I (TOP1): DNA damage repair and anticancer therapy. Biomol Ther 5(3):1652–1670. https://doi.org/10.3390/biom5031652
Durand-Dubief M, Persson J, Norman U et al (2010) Topoisomerase I regulates open chromatin and controls gene expression in vivo. EMBO J 29(13):2126–2134. https://doi.org/10.1038/emboj.2010.109
Marinello J, Chillemi G, Bueno S et al (2013) Antisense transcripts enhanced by camptothecin at divergent CpG-island promoters associated with bursts of topoisomerase I-DNA cleavage complex and R-loop formation. Nucleic Acids Res 41(22):10110–10123. https://doi.org/10.1093/nar/gkt778
Puc J, Kozbial P, Li W et al (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160(3):367–380. https://doi.org/10.1016/j.cell.2014.12.023
Marinello J, Bertoncini S, Aloisi I et al (2016) Dynamic effects of topoisomerase I inhibition on R-loops and short transcripts at active promoters. PLoS One 11(1):e0147053. https://doi.org/10.1371/journal.pone.0147053
Rosenberg M, Fan AX, Lin IJ et al (2013) Cell-cycle specific association of transcription factors and RNA polymerase II with the human beta-globin gene locus. J Cell Biochem 114(9):1997–2006. https://doi.org/10.1002/jcb.24542
Baranello L, Wojtowicz D, Cui K et al (2016) RNA polymerase II regulates topoisomerase 1 activity to favor efficient transcription. Cell 165(2):357–371. https://doi.org/10.1016/j.cell.2016.02.036
Phatnani HP, Greenleaf AL (2004) Identifying phosphoCTD-associating proteins. Methods Mol Biol 257:17–28. https://doi.org/10.1385/1-59259-750-5:017
Wu J, Phatnani HP, Hsieh TS et al (2010) The phosphoCTD-interacting domain of topoisomerase I. Biochem Biophys Res Commun 397(1):117–119. https://doi.org/10.1016/j.bbrc.2010.05.081
Husain A, Begum NA, Taniguchi T et al (2016) Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability. Nat Commun 7:10549. https://doi.org/10.1038/ncomms10549
Zylka MJ, Simon JM, Philpot BD (2015) Gene length matters in neurons. Neuron 86(2):353–355. https://doi.org/10.1016/j.neuron.2015.03.059
King IF, Yandava CN, Mabb AM et al (2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501(7465):58–62. https://doi.org/10.1038/nature12504
Mabb AM, Simon JM, King IF et al (2016) Topoisomerase 1 regulates gene expression in neurons through cleavage complex-dependent and -independent mechanisms. PLoS One 11(5):e0156439. https://doi.org/10.1371/journal.pone.0156439
Solier S, Ryan MC, Martin SE et al (2013) Transcription poisoning by topoisomerase I is controlled by gene length, splice sites, and miR-142-3p. Cancer Res 73(15):4830–4839. https://doi.org/10.1158/0008-5472.CAN-12-3504
Chan YA, Aristizabal MJ, Lu PY et al (2014) Genome-wide profiling of yeast DNA:RNA hybrid prone sites with DRIP-Chip. PLoS Genet 10(4):e1004288. https://doi.org/10.1371/journal.pgen.1004288
Wahba L, Amon JD, Koshland D et al (2011) RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol Cell 44(6):978–988. https://doi.org/10.1016/j.molcel.2011.10.017
Wahba L, Costantino L, Tan FJ et al (2016) S1-DRIP-seq identifies high expression and polyA tracts as major contributors to R-loop formation. Genes Dev 30(11):1327–1338. https://doi.org/10.1101/gad.280834.116
Rossi F, Labourier E, Forne T et al (1996) Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381(6577):80–82. https://doi.org/10.1038/381080a0
Labourier E, Rossi F, Gallouzi IE et al (1998) Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor. Nucleic Acids Res 26(12):2955–2962
Soret J, Gabut M, Dupon C et al (2003) Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in mammalian cells lacking topoisomerase I. Cancer Res 63(23):8203–8211
Malanga M, Czubaty A, Girstun A et al (2008) Poly(ADP-ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. J Biol Chem 283(29):19991–19998. https://doi.org/10.1074/jbc.M709495200
Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12(3):711–721
Strasser K, Masuda S, Mason P et al (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417(6886):304–308. https://doi.org/10.1038/nature746
Luna R, Rondon AG, Aguilera A (2012) New clues to understand the role of THO and other functionally related factors in mRNP biogenesis. Biochim Biophys Acta 1819(6):514–520. https://doi.org/10.1016/j.bbagrm.2011.11.012
Gowrishankar J, Harinarayanan R (2004) Why is transcription coupled to translation in bacteria? Mol Microbiol 54(3):598–603. https://doi.org/10.1111/j.1365-2958.2004.04289.x
Leela JK, Syeda AH, Anupama K et al (2013) Rho-dependent transcription termination is essential to prevent excessive genome-wide R-loops in Escherichia coli. Proc Natl Acad Sci U S A 110(1):258–263. https://doi.org/10.1073/pnas.1213123110
El Hage A, French SL, Beyer AL et al (2010) Loss of topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis. Genes Dev 24(14):1546–1558. https://doi.org/10.1101/gad.573310
Gan W, Guan Z, Liu J et al (2011) R-loop-mediated genomic instability is caused by impairment of replication fork progression. Genes Dev 25(19):2041–2056. https://doi.org/10.1101/gad.17010011
Wellinger RE, Prado F, Aguilera A (2006) Replication fork progression is impaired by transcription in hyperrecombinant yeast cells lacking a functional THO complex. Mol Cell Biol 26(8):3327–3334. https://doi.org/10.1128/MCB.26.8.3327-3334.2006
Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16(1):2–9. https://doi.org/10.1038/ncb2897
Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBS J 276(6):1494–1505. https://doi.org/10.1111/j.1742-4658.2009.06908.x
Mischo HE, Gomez-Gonzalez B, Grzechnik P et al (2011) Yeast Sen1 helicase protects the genome from transcription-associated instability. Mol Cell 41(1):21–32. https://doi.org/10.1016/j.molcel.2010.12.007
Skourti-Stathaki K, Proudfoot NJ, Gromak N (2011) Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42(6):794–805. https://doi.org/10.1016/j.molcel.2011.04.026
Li X, Manley JL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122(3):365–378. https://doi.org/10.1016/j.cell.2005.06.008
Aguilera A, Garcia-Muse T (2012) R loops: from transcription byproducts to threats to genome stability. Mol Cell 46(2):115–124. https://doi.org/10.1016/j.molcel.2012.04.009
Skourti-Stathaki K, Proudfoot NJ (2014) A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev 28(13):1384–1396. https://doi.org/10.1101/gad.242990.114
Hamperl S, Cimprich KA (2014) The contribution of co-transcriptional RNA:DNA hybrid structures to DNA damage and genome instability. DNA Repair 19:84–94. https://doi.org/10.1016/j.dnarep.2014.03.023
Sollier J, Cimprich KA (2015) Breaking bad: R-loops and genome integrity. Trends Cell Biol 25(9):514–522. https://doi.org/10.1016/j.tcb.2015.05.003
Tuduri S, Crabbe L, Conti C et al (2009) Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat Cell Biol 11(11):1315–1324. https://doi.org/10.1038/ncb1984
Ribeyre C, Zellweger R, Chauvin M et al (2016) Nascent DNA proteomics reveals a chromatin remodeler required for topoisomerase I loading at replication forks. Cell Rep 15(2):300–309. https://doi.org/10.1016/j.celrep.2016.03.027
Christman MF, Dietrich FS, Fink GR (1988) Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA topoisomerases I and II. Cell 55(3):413–425
Houseley J, Kotovic K, El Hage A et al (2007) Trf4 targets ncRNAs from telomeric and rDNA spacer regions and functions in rDNA copy number control. EMBO J 26(24):4996–5006. https://doi.org/10.1038/sj.emboj.7601921
Krawczyk C, Dion V, Schar P et al (2014) Reversible Top1 cleavage complexes are stabilized strand-specifically at the ribosomal replication fork barrier and contribute to ribosomal DNA stability. Nucleic Acids Res 42(8):4985–4995. https://doi.org/10.1093/nar/gku148
Trigueros S, Roca J (2002) Failure to relax negative supercoiling of DNA is a primary cause of mitotic hyper-recombination in topoisomerase-deficient yeast cells. J Biol Chem 277(40):37207–37211. https://doi.org/10.1074/jbc.M206663200
Tornaletti S, Park-Snyder S, Hanawalt PC (2008) G4-forming sequences in the non-transcribed DNA strand pose blocks to T7 RNA polymerase and mammalian RNA polymerase II. J Biol Chem 283(19):12756–12762. https://doi.org/10.1074/jbc.M705003200
Lopes J, Piazza A, Bermejo R et al (2011) G-quadruplex-induced instability during leading-strand replication. EMBO J 30(19):4033–4046. https://doi.org/10.1038/emboj.2011.316
London TB, Barber LJ, Mosedale G et al (2008) FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts. J Biol Chem 283(52):36132–36139. https://doi.org/10.1074/jbc.M808152200
Paeschke K, Capra JA, Zakian VA (2011) DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145(5):678–691. https://doi.org/10.1016/j.cell.2011.04.015
Kim N, Jinks-Robertson S (2011) Guanine repeat-containing sequences confer transcription-dependent instability in an orientation-specific manner in yeast. DNA Repair 10(9):953–960. https://doi.org/10.1016/j.dnarep.2011.07.002
Yadav P, Harcy V, Argueso JL et al (2014) Topoisomerase I plays a critical role in suppressing genome instability at a highly transcribed G-quadruplex-forming sequence. PLoS Genet 10(12):e1004839. https://doi.org/10.1371/journal.pgen.1004839
Yadav P, Owiti N, Kim N (2016) The role of topoisomerase I in suppressing genome instability associated with a highly transcribed guanine-rich sequence is not restricted to preventing RNA:DNA hybrid accumulation. Nucleic Acids Res 44(2):718–729. https://doi.org/10.1093/nar/gkv1152
Arimondo PB, Riou JF, Mergny JL et al (2000) Interaction of human DNA topoisomerase I with G-quartet structures. Nucleic Acids Res 28(24):4832–4838
Marchand C, Pourquier P, Laco GS et al (2002) Interaction of human nuclear topoisomerase I with guanosine quartet-forming and guanosine-rich single-stranded DNA and RNA oligonucleotides. J Biol Chem 277(11):8906–8911. https://doi.org/10.1074/jbc.M106372200
Shuai L, Deng M, Zhang D et al (2010) Quadruplex-duplex motifs as new topoisomerase I inhibitors. Nucleosides Nucleotides Nucleic Acids 29(11):841–853. https://doi.org/10.1080/15257770.2010.530635
Gazumyan A, Bothmer A, Klein IA et al (2012) Activation-induced cytidine deaminase in antibody diversification and chromosome translocation. Adv Cancer Res 113:167–190. https://doi.org/10.1016/b978-0-12-394280-7.00005-1
Matthews AJ, Zheng S, DiMenna LJ et al (2014) Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv Immunol 122:1–57. https://doi.org/10.1016/b978-0-12-800267-4.00001-8
Hwang JK, Alt FW, Yeap LS (2015) Related mechanisms of antibody somatic hypermutation and class switch recombination. Microbiol Spectr 3(1):Mdna3-0037-2014. https://doi.org/10.1128/microbiolspec.MDNA3-0037-2014
Senavirathne G, Bertram JG, Jaszczur M et al (2015) Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution. Nat Commun 6:10209. https://doi.org/10.1038/ncomms10209
Huang FT, Yu K, Balter BB et al (2007) Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol Cell Biol 27(16):5921–5932. https://doi.org/10.1128/mcb.00702-07
Ruiz JF, Gomez-Gonzalez B, Aguilera A (2011) AID induces double-strand breaks at immunoglobulin switch regions and c-MYC causing chromosomal translocations in yeast THO mutants. PLoS Genet 7(2):e1002009. https://doi.org/10.1371/journal.pgen.1002009
Kobayashi M, Aida M, Nagaoka H et al (2009) AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. Proc Natl Acad Sci U S A 106(52):22375–22380. https://doi.org/10.1073/pnas.0911879106
Kobayashi M, Sabouri Z, Sabouri S et al (2011) Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Proc Natl Acad Sci U S A 108(48):19305–19310. https://doi.org/10.1073/pnas.1114522108
Ronai D, Iglesias-Ussel MD, Fan M et al (2007) Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J Exp Med 204(1):181–190. https://doi.org/10.1084/jem.20062032
Maul RW, Saribasak H, Cao Z et al (2015) Topoisomerase I deficiency causes RNA polymerase II accumulation and increases AID abundance in immunoglobulin variable genes. DNA Repair 30:46–52. https://doi.org/10.1016/j.dnarep.2015.03.004
Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6(10):743–755. https://doi.org/10.1038/nrg1691
La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11(4):247–258. https://doi.org/10.1038/nrg2748
Wojciechowska M, Krzyzosiak WJ (2011) CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. RNA Biol 8(4):565–571. https://doi.org/10.4161/rna.8.4.15397
Hubert L Jr, Lin Y, Dion V et al (2011) Topoisomerase 1 and single-strand break repair modulate transcription-induced CAG repeat contraction in human cells. Mol Cell Biol 31(15):3105–3112. https://doi.org/10.1128/mcb.05158-11
Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9(8):619–631. https://doi.org/10.1038/nrg2380
Takahashi T, Burguiere-Slezak G, Van der Kemp PA et al (2011) Topoisomerase 1 provokes the formation of short deletions in repeated sequences upon high transcription in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 108(2):692–697. https://doi.org/10.1073/pnas.1012582108
Lippert MJ, Kim N, Cho JE et al (2011) Role for topoisomerase 1 in transcription-associated mutagenesis in yeast. Proc Natl Acad Sci U S A 108(2):698–703. https://doi.org/10.1073/pnas.1012363108
Nick McElhinny SA, Watts BE, Kumar D et al (2010) Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. Proc Natl Acad Sci U S A 107(11):4949–4954. https://doi.org/10.1073/pnas.0914857107
Nick McElhinny SA, Kumar D, Clark AB et al (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6(10):774–781. https://doi.org/10.1038/nchembio.424
Lujan SA, Williams JS, Clausen AR et al (2013) Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol Cell 50(3):437–443. https://doi.org/10.1016/j.molcel.2013.03.017
Williams JS, Clausen AR, Lujan SA et al (2015) Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific. Nat Struct Mol Biol 22(4):291–297. https://doi.org/10.1038/nsmb.2989
Sparks JL, Chon H, Cerritelli SM et al (2012) RNase H2-initiated ribonucleotide excision repair. Mol Cell 47(6):980–986. https://doi.org/10.1016/j.molcel.2012.06.035
Kim N, Huang SN, Williams JS et al (2011) Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332(6037):1561–1564. https://doi.org/10.1126/science.1205016
Clark AB, Lujan SA, Kissling GE et al (2011) Mismatch repair-independent tandem repeat sequence instability resulting from ribonucleotide incorporation by DNA polymerase ε. DNA Repair 10(5):476–482. https://doi.org/10.1016/j.dnarep.2011.02.001
Potenski CJ, Niu H, Sung P et al (2014) Avoidance of ribonucleotide-induced mutations by RNase H2 and Srs2-Exo1 mechanisms. Nature 511(7508):251–254. https://doi.org/10.1038/nature13292
Niu H, Potenski CJ, Epshtein A et al (2016) Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA. Cell Cycle 15(3):331–336. https://doi.org/10.1080/15384101.2015.1128594
Williams JS, Smith DJ, Marjavaara L et al (2013) Topoisomerase 1-mediated removal of ribonucleotides from nascent leading-strand DNA. Mol Cell 49(5):1010–1015. https://doi.org/10.1016/j.molcel.2012.12.021
Sekiguchi J, Shuman S (1997) Site-specific ribonuclease activity of eukaryotic DNA topoisomerase I. Mol Cell 1(1):89–97
Cho JE, Kim N, Li YC et al (2013) Two distinct mechanisms of topoisomerase 1-dependent mutagenesis in yeast. DNA Repair 12(3):205–211. https://doi.org/10.1016/j.dnarep.2012.12.004
Sparks JL, Burgers PM (2015) Error-free and mutagenic processing of topoisomerase 1-provoked damage at genomic ribonucleotides. EMBO J 34(9):1259–1269. 10.15252/embj.201490868
Huang SY, Ghosh S, Pommier Y (2015) Topoisomerase I alone is sufficient to produce short DNA deletions and can also reverse nicks at ribonucleotide sites. J Biol Chem 290(22):14068–14076. https://doi.org/10.1074/jbc.M115.653345
Cho JE, Huang SN, Burgers PM et al (2016) Parallel analysis of ribonucleotide-dependent deletions produced by yeast Top1 in vitro and in vivo. Nucleic Acids Res 44(16):7714–7721. https://doi.org/10.1093/nar/gkw495
Cho JE, Kim N, Jinks-Robertson S (2015) Topoisomerase 1-dependent deletions initiated by incision at ribonucleotides are biased to the non-transcribed strand of a highly activated reporter. Nucleic Acids Res 43(19):9306–9313. https://doi.org/10.1093/nar/gkv824
Cho JE, Jinks-Robertson S (2016) Ribonucleotides and transcription-associated mutagenesis in yeast. J Mol Biol. https://doi.org/10.1016/j.jmb.2016.08.005
Stewart L, Redinbo MR, Qiu X et al (1998) A model for the mechanism of human topoisomerase I. Science 279(5356):1534–1541
Wu J, Liu LF (1997) Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res 25(21):4181–4186
Conover HN, Lujan SA, Chapman MJ et al (2015) Stimulation of chromosomal rearrangements by ribonucleotides. Genetics 201(3):951–961. https://doi.org/10.1534/genetics.115.181149
Epshtein A, Potenski CJ, Klein HL (2016) Increased spontaneous recombination in RNase H2-deficient cells arises from multiple contiguous rNMPs and not from single rNMP residues incorporated by DNA polymerase epsilon. Microb Cell 3(6):248–254
Allen-Soltero S, Martinez SL, Putnam CD et al (2014) A Saccharomyces cerevisiae RNase H2 interaction network functions to suppress genome instability. Mol Cell Biol 34(8):1521–1534. https://doi.org/10.1128/mcb.00960-13
Mankouri HW, Ngo HP, Hickson ID (2009) Esc2 and Sgs1 act in functionally distinct branches of the homologous recombination repair pathway in Saccharomyces cerevisiae. Mol Biol Cell 20(6):1683–1694. https://doi.org/10.1091/mbc.E08-08-0877
Ii M, Ii T, Mironova LI et al (2011) Epistasis analysis between homologous recombination genes in Saccharomyces cerevisiae identifies multiple repair pathways for Sgs1, Mus81-Mms4 and RNase H2. Mutat Res 714(1–2):33–43. https://doi.org/10.1016/j.mrfmmm.2011.06.007
Chon H, Sparks JL, Rychlik M et al (2013) RNase H2 roles in genome integrity revealed by unlinking its activities. Nucleic Acids Res 41(5):3130–3143. https://doi.org/10.1093/nar/gkt027
Llorente B, Smith CE, Symington LS (2008) Break-induced replication: what is it and what is it for? Cell Cycle 7(7):859–864. https://doi.org/10.4161/cc.7.7.5613
O’Connell K, Jinks-Robertson S, Petes TD (2015) Elevated genome-wide instability in yeast mutants lacking RNase H activity. Genetics 201(3):963–975. https://doi.org/10.1534/genetics.115.182725
Shuman S, Turner J (1993) Site-specific interaction of vaccinia virus topoisomerase I with base and sugar moieties in duplex DNA. J Biol Chem 268(25):18943–18950
Been MD, Champoux JJ (1984) Breakage of single-stranded DNA by eukaryotic type 1 topoisomerase occurs only at regions with the potential for base-pairing. J Mol Biol 180(3):515–531
Waters CA, Strande NT, Wyatt DW et al (2014) Nonhomologous end joining: a good solution for bad ends. DNA Repair 17:39–51. https://doi.org/10.1016/j.dnarep.2014.02.008
Christiansen K, Svejstrup AB, Andersen AH et al (1993) Eukaryotic topoisomerase I-mediated cleavage requires bipartite DNA interaction. Cleavage of DNA substrates containing strand interruptions implicates a role for topoisomerase I in illegitimate recombination. J Biol Chem 268(13):9690–9701
Henningfeld KA, Hecht SM (1995) A model for topoisomerase I-mediated insertions and deletions with duplex DNA substrates containing branches, nicks, and gaps. Biochemistry 34(18):6120–6129
Bullock P, Champoux JJ, Botchan M (1985) Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science 230(4728):954–958
Kovac MB, Kovacova M, Bachraty H et al (2015) High-resolution breakpoint analysis provides evidence for the sequence-directed nature of genome rearrangements in hereditary disorders. Hum Mutat 36(2):250–259. https://doi.org/10.1002/humu.22734
Zhu J, Schiestl RH (1996) Topoisomerase I involvement in illegitimate recombination in Saccharomyces cerevisiae. Mol Cell Biol 16:1805–1812
Zhu J, Schiestl RH (2004) Human topoisomerase I mediates illegitimate recombination leading to DNA insertion into the ribosomal DNA locus in Saccharomyces cerevisiae. Mol Gen Genomics 271(3):347–358. https://doi.org/10.1007/s00438-004-0987-7
Pommier Y, Jenkins J, Kohlhagen G et al (1995) DNA recombinase activity of eukaryotic DNA topoisomerase I; effects of camptothecin and other inhibitors. Mutat Res 337(2):135–145
Behrendt R, Roers A (2014) Mouse models for Aicardi-Goutières syndrome provide clues to the molecular pathogenesis of systemic autoimmunity. Clin Exp Immunol 175(1):9–16. https://doi.org/10.1111/cei.12147
Lim YW, Sanz LA, Xu X et al (2015) Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome. elife 4. https://doi.org/10.7554/eLife.08007
Li M, Pokharel S, Wang JT et al (2015) RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability. Nat Commun 6:6720. https://doi.org/10.1038/ncomms7720
Li M, Liu Y (2016) Topoisomerase I in human disease pathogenesis and treatments. Genomics Proteomics Bioinformatics 14(3):166–171. https://doi.org/10.1016/j.gpb.2016.02.004
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Cho, JE., Jinks-Robertson, S. (2018). Topoisomerase I and Genome Stability: The Good and the Bad. In: Drolet, M. (eds) DNA Topoisomerases. Methods in Molecular Biology, vol 1703. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7459-7_2
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7459-7_2
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7458-0
Online ISBN: 978-1-4939-7459-7
eBook Packages: Springer Protocols